CD1 proteins (CD1a, CD1b, CD1c, CD1d) present lipid antigens for specific interactions with the T cell antigen receptor (TCR). This represents a fundamentally new cellular pathway leading to T cell activation and significantly expands the range of antigens recognized by T cells. The applicant's preliminary results define the first structure of a CD1c-presented antigen to be mannosyl phosphodolichol (MPD), a member of a class of long chain isoprenoid lipids that are present in all cellular organisms. Preliminary studies indicated that the TCR and CD1c mediated human T cell responses to semi-synthetic analogs of both foreign (mycobacterial) and self (human) MPD, thus defining a lipid autoantigen for alphabeta T cells. A trimolecular model of this recognition predicts that CD1 presents amphipathic glycolipids by sequestering the lipid within the hydrophobic groove of CD1, resulting in presentation of the carbohydrate moiety of the antigen to the TCR. The proposed studies will test this model by preparing isoprenoid glycolipids that differ in glycosylation, saturation branching and length of the lipid. Antigen analogs will be tested in plasmon resonance, scintillation proximity and cell-based assays to determine the role of antigen structure in the separate processes of CD1c binding and T cell activation. In particular, analogs will e synthesize to define the structures that distinguish CD1c ligands from those presented by CD1b and CD1d and to determine the molecular basis of discrimination of self from foreign MPDs. We propose a new model of glycolipid autoimmunity by which human autoreactive T cells recognize self isoprenoid glycolipids bound to the CD1c protein. These studies will provide a basic understanding of the molecular events underlying CD1c-presentation of lipids to the TCR and the cellular basis of presentation of a lipid autoantigen.